title: Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase.
abstract: The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
authors.affiliation: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, California 94304, United States. David-M.Goldstein@roche.com
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Michael
authors.initials: M
authors.lastname: Soth
authors.forename: Tobias
authors.initials: T
authors.lastname: Gabriel
authors.forename: Nolan
authors.initials: N
authors.lastname: Dewdney
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Humberto
authors.initials: H
authors.lastname: Arzeno
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Bingenheimer
authors.forename: Stacie A
authors.initials: SA
authors.lastname: Dalrymple
authors.forename: James
authors.initials: J
authors.lastname: Dunn
authors.forename: Robert
authors.initials: R
authors.lastname: Farrell
authors.forename: Sandra
authors.initials: S
authors.lastname: Frauchiger
authors.forename: JoAnn
authors.initials: J
authors.lastname: La Fargue
authors.forename: Manjiri
authors.initials: M
authors.lastname: Ghate
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.forename: Fujun
authors.initials: F
authors.lastname: Li
authors.forename: Renee
authors.initials: R
authors.lastname: Litman
authors.forename: Brad
authors.initials: B
authors.lastname: Loe
authors.forename: Joel
authors.initials: J
authors.lastname: McIntosh
authors.forename: Daniel
authors.initials: D
authors.lastname: McWeeney
authors.forename: Eva
authors.initials: E
authors.lastname: Papp
authors.forename: Jaehyeon
authors.initials: J
authors.lastname: Park
authors.forename: Harlan F
authors.initials: HF
authors.lastname: Reese
authors.forename: Richard T
authors.initials: RT
authors.lastname: Roberts
authors.forename: David
authors.initials: D
authors.lastname: Rotstein
authors.forename: Bong
authors.initials: B
authors.lastname: San Pablo
authors.forename: Keshab
authors.initials: K
authors.lastname: Sarma
authors.forename: Martin
authors.initials: M
authors.lastname: Stahl
authors.forename: Man-Ling
authors.initials: ML
authors.lastname: Sung
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Suttman
authors.forename: Eric B
authors.initials: EB
authors.lastname: Sjogren
authors.forename: Yunchou
authors.initials: Y
authors.lastname: Tan
authors.forename: Alejandra
authors.initials: A
authors.lastname: Trejo
authors.forename: Mary
authors.initials: M
authors.lastname: Welch
authors.forename: Paul
authors.initials: P
authors.lastname: Weller
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
authors.forename: Hasim
authors.initials: H
authors.lastname: Zecic
mesh_terms: D000284:Administration, Oral; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001682:Biological Availability; D002460:Cell Line; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C558595:6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido(2,3-d)pyrimidin-7(8H)-one; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C533858:pamapimod; D048308:Mitogen-Activated Protein Kinase 14